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Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma

Key Points

  • Allergic diseases — such as allergic rhinitis, asthma and atopic dermatitis — have diverse clinical features, but they have analogous immunological characteristics. Patients show upregulation of allergen-specific CD4+ T helper 2 (TH2) cells and allergen-specific IgE.

  • Strategies to promote long-term relief from the symptoms of allergic disease aim to inhibit allergen-specific TH2-cytokine responses.

  • Recently, several T-cell populations with the capacity to regulate immune responses have been described. These are known as regulatory T cells, and evidence is emerging that the function of regulatory T cells might be impaired in some allergic diseases.

  • Interleukin-10 (IL-10) is an anti-inflammatory cytokine, and it is produced by some populations of regulatory T cells (called IL-10-secreting regulatory T cells), as well as by antigen-presenting cells. It is an attractive candidate for the treatment of allergic asthma.

  • Some existing therapies for allergic diseases — both non-specific therapies, such as treatment with glucocorticoids, and specific therapies, such as allergen-desensitization immunotherapy — might function, at least in part, to promote the function of IL-10-secreting regulatory T cells.

  • Novel approaches that build on these observations are discussed, both experimental and those being tested in clinical trials.

Abstract

Allergic diseases are caused by aberrant T-helper-2 immune responses in susceptible individuals. Both naturally occurring CD4+CD25+ regulatory T cells and inducible populations of antigen-specific interleukin-10-secreting regulatory T cells inhibit these inappropriate immune responses in experimental models. This article discusses the evidence that regulatory T-cell function might be impaired in allergic and asthmatic disease and that certain therapeutic regimens might function, at least in part, to promote regulatory T-cell generation. Current research strategies seek to exploit these observations to improve the generation of allergen-specific regulatory T-cell populations with the potential to provide the safe and long-term alleviation of disease symptoms.

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Figure 1: Allergic mechanisms.
Figure 2: The allergic pathway and potential points of intervention.
Figure 3: Functions of interleukin-10 that are relevant to allergy and asthma.

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References

  1. Kay, A. B. Allergy and allergic diseases. First of two parts. N. Engl. J. Med. 344, 30–37 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Holgate, S. T. & Broide, D. New targets for allergic rhinitis — a disease of civilization. Nature Rev. Drug Discov. 2, 902–914 (2003).

    Google Scholar 

  3. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 351, 1225–1232 (1998).

  4. Burney, P. et al. The distribution of total and specific serum IgE in the European Community Respiratory Health Survey. J. Allergy Clin. Immunol. 99, 314–322 (1997).

    CAS  PubMed  Google Scholar 

  5. Robinson, D. S. TH2 cytokines in allergic disease. Br. Med. Bull. 56, 956–968 (2000).

    CAS  PubMed  Google Scholar 

  6. Cookson, W. & Moffatt, M. Making sense of asthma genes. N. Engl. J. Med. 351, 1794–1796 (2004).

    CAS  PubMed  Google Scholar 

  7. Wills-Karp, M., Santeliz, J. & Karp, C. L. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nature Rev. Immunol. 1, 69–75 (2001).

    CAS  Google Scholar 

  8. Mosmann, T. R. & Coffman, R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).

    CAS  PubMed  Google Scholar 

  9. Romagnani, S. Regulation of the development of type 2 T-helper cells in allergy. Curr. Opin. Immunol. 6, 838–846 (1994).

    CAS  PubMed  Google Scholar 

  10. Robinson, D. S. et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 326, 298–304 (1992). This is an important early study that showed the presence of T H 2-cytokine-mRNA-positive T cells in the lungs of patients with allergic asthma.

    CAS  PubMed  Google Scholar 

  11. Bentley, A. M. et al. Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies after allergen inhalation challenge in atopic asthmatics. Am. J. Respir. Cell Mol. Biol. 8, 35–42 (1993).

    CAS  PubMed  Google Scholar 

  12. Lloyd, C. M., Gonzalo, J. A., Coyle, A. J. & Gutierrez-Ramos, J. C. Mouse models of allergic airway disease. Adv. Immunol. 77, 263–295 (2001).

    CAS  PubMed  Google Scholar 

  13. Barnes, P. J. Current therapies for asthma. Promise and limitations. Chest 111, 17S–26S (1997).

    CAS  PubMed  Google Scholar 

  14. Maloy, K. J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nature Immunol. 2, 816–822 (2001).

    CAS  Google Scholar 

  15. Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004).

    CAS  PubMed  Google Scholar 

  16. O'Garra, A. & Vieira, P. Regulatory T cells and mechanisms of immune system control. Nature Med. 10, 801–805 (2004).

    CAS  PubMed  Google Scholar 

  17. Shevach, E. CD4+CD25+ suppressor T cells: more questions than answers. Nature Rev. Immunol. 2, 389–400 (2002). References 14–17 are key reviews that describe naturally occurring and antigen-driven regulatory T cells, and they refer to the important original papers in this field.

    CAS  Google Scholar 

  18. Annacker, O. et al. CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J. Immunol. 166, 3008–3018 (2001).

    CAS  PubMed  Google Scholar 

  19. Maloy, K. J. et al. CD4+CD25+ TR cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Jordan, M. S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nature Immunol. 2, 301–306 (2001).

    CAS  Google Scholar 

  21. Apostolou, I. & Von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Baecher-Allan, C., Viglietta, V. & Hafler, D. A. Inhibition of human CD4+CD25+high regulatory T cell function. J. Immunol. 169, 6210–6217 (2002).

    CAS  PubMed  Google Scholar 

  23. Sakaguchi, S. et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev. 182, 18–32 (2001).

    CAS  PubMed  Google Scholar 

  24. Read, S., Malmstrom, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303–310 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. & Sakaguchi, S. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nature Immunol. 3, 135–142 (2002).

    CAS  Google Scholar 

  27. McHugh, R. S. et al. CD4+CD25+ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311–323 (2002).

    CAS  PubMed  Google Scholar 

  28. Green, E. A., Gorelik, L., McGregor, C. M., Tran, E. H. & Flavell, R. A. CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-β–TGF-β receptor interactions in type 1 diabetes. Proc. Natl Acad. Sci. USA 100, 10878–10883 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Belkaid, Y., Piccirillo, C. A., Mendez, S., Shevach, E. M. & Sacks, D. L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002).

    CAS  PubMed  Google Scholar 

  31. Suri-Payer, E. & Cantor, H. Differential cytokine requirements for regulation of autoimmune gastritis and colitis by CD4+CD25+ T cells. J. Autoimmun. 16, 115–123 (2001).

    CAS  PubMed  Google Scholar 

  32. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    CAS  PubMed  Google Scholar 

  33. Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nature Immunol. 4, 337–342 (2003).

    CAS  Google Scholar 

  34. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003). References 32–34 were the first to describe the transcription factor FOXP3 and its role in the development of naturally occurring T Reg cells.

    CAS  Google Scholar 

  35. Ramsdell, F. Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity 19, 165–168 (2003).

    CAS  PubMed  Google Scholar 

  36. Yagi, H. et al. Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int. Immunol. 16, 1643–1656 (2004).

    CAS  PubMed  Google Scholar 

  37. Chen, W. et al. Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Walker, M. R. et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25 T cells. J. Clin. Invest. 112, 1437–1443 (2003).

    CAS  PubMed  Google Scholar 

  39. Powrie, F. et al. Inhibition of TH1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1, 553–562 (1994).

    CAS  PubMed  Google Scholar 

  40. Liu, H., Hu, B., Xu, D. & Liew, F. Y. CD4+CD25+ regulatory T cells cure murine colitis: the role of IL-10, TGF-β, and CTLA4. J. Immunol. 171, 5012–5017 (2003).

    CAS  PubMed  Google Scholar 

  41. Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).

    CAS  PubMed  Google Scholar 

  42. Hara, M. et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J. Immunol. 166, 3789–3796 (2001).

    CAS  PubMed  Google Scholar 

  43. Kingsley, C. I., Karim, M., Bushell, A. R. & Wood, K. J. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J. Immunol. 168, 1080–1086 (2002).

    CAS  PubMed  Google Scholar 

  44. Shimizu, J., Yamazaki, S. & Sakaguchi, S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J. Immunol. 163, 5211–5218 (1999).

    CAS  PubMed  Google Scholar 

  45. Golgher, D., Jones, E., Powrie, F., Elliott, T. & Gallimore, A. Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens. Eur. J. Immunol. 32, 3267–3275 (2002).

    CAS  PubMed  Google Scholar 

  46. Xu, D. et al. CD4+CD25+ regulatory T cells suppress differentiation and functions of TH1 and TH2 cells, Leishmania major infection, and colitis in mice. J. Immunol. 170, 394–399 (2003).

    CAS  PubMed  Google Scholar 

  47. Stassen, M. et al. Differential regulatory capacity of CD25+ T regulatory cells and preactivated CD25+ T regulatory cells on development, functional activation, and proliferation of TH2 cells. J. Immunol. 173, 267–274 (2004).

    CAS  PubMed  Google Scholar 

  48. Kinter, A. L. et al. CD25+CD4+ regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4+ and CD8+ HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J. Exp. Med. 200, 331–343 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Aandahl, E. M., Michaelsson, J., Moretto, W. J., Hecht, F. M. & Nixon, D. F. Human CD4+ CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus antigens. J. Virol. 78, 2454–2459 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Oswald-Richter, K. et al. HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells. PLoS Biol. 2, E198 (2004).

    PubMed  PubMed Central  Google Scholar 

  51. Hadeiba, H. & Locksley, R. M. Lung CD25 CD4 regulatory T cells suppress type 2 immune responses but not bronchial hyperreactivity. J. Immunol. 170, 5502–5510 (2003).

    CAS  PubMed  Google Scholar 

  52. Bellinghausen, I., Klostermann, B., Knop, J. & Saloga, J. Human CD4+CD25+ T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production. J. Allergy Clin. Immunol. 111, 862–868 (2003).

    CAS  PubMed  Google Scholar 

  53. Ling, E. M. et al. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363, 608–615 (2004). References 52 and 53 were the first to indicate that there might be a defect in the function of naturally occurring T Reg cells in patients with active allergic disease. Reference 53 also indicates that active suppression of allergen-specific T H 2 responses occurs in healthy, non-atopic individuals.

    CAS  PubMed  Google Scholar 

  54. O'Garra, A., Vieira, P. L., Vieira, P. & Goldfeld, A. E. IL-10-producing and naturally occurring CD4+ TRegs: limiting collateral damage. J. Clin. Invest. 114, 1372–1378 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Read, S. et al. CD38+ CD45RBlow CD4+ T cells: a population of T cells with immune regulatory activities in vitro. Eur. J. Immunol. 28, 3435–3447 (1998).

    CAS  PubMed  Google Scholar 

  56. Asseman, C., Read, S. & Powrie, F. Colitogenic TH1 cells are present in the antigen-experienced T cell pool in normal mice: control by CD4+ regulatory T cells and IL-10. J. Immunol. 171, 971–978 (2003).

    CAS  PubMed  Google Scholar 

  57. Sundstedt, A. et al. Immunoregulatory role of IL-10 during superantigen-induced hyporesponsiveness in vivo. J. Immunol. 158, 180–186 (1997).

    CAS  PubMed  Google Scholar 

  58. Sundstedt, A., O'Neill, E. J., Nicolson, K. S. & Wraith, D. C. Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J. Immunol. 170, 1240–1248 (2003).

    CAS  PubMed  Google Scholar 

  59. Groux, H. et al. Generation of a novel regulatory CD4+ T-cell population, which inhibits antigen-specific T-cell responses. Nature 389, 737–742 (1997).

    CAS  PubMed  Google Scholar 

  60. Levings, M. K. et al. IFN-α and IL-10 induce the differentiation of human type 1 T regulatory cells. J. Immunol. 166, 5530–5539 (2001).

    CAS  PubMed  Google Scholar 

  61. Buer, J. et al. Interleukin 10 secretion and impaired effector function of major histocompatibility complex class II-restricted T cells anergized in vivo. J. Exp. Med. 187, 177–183 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Barrat, F. J. et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (TH1)- and TH2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002). This study describes the in vitro generation, using immunosuppressive drugs, of homogeneous populations of IL-10-secreting regulatory T cells that do not produce T H 1 or T H 2 cytokines, which has implications for immunotherapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Pontoux, C., Banz, A. & Papiernik, M. Natural CD4 CD25+ regulatory T cells control the burst of superantigen-induced cytokine production: the role of IL-10. Int. Immunol. 14, 233–239 (2002).

    CAS  PubMed  Google Scholar 

  64. Weiner, H. L. Induction and mechanism of action of transforming growth factor-β-secreting TH3 regulatory cells. Immunol. Rev. 182, 207–214 (2001).

    CAS  PubMed  Google Scholar 

  65. Kemper, C. et al. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 421, 388–392 (2003).

    CAS  PubMed  Google Scholar 

  66. Bacchetta, R. et al. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J. Exp. Med. 179, 493–502 (1994). This is an important early study that describes that high endogenous IL-10 production is a general phenomenon in patients with SCID in whom allogeneic haematopoietic stem-cell transplantation results in immunological reconstitution and induction of tolerance. This has been a seminal paper in the current resurgence of interest in the therapeutic applications of regulatory T cells.

    CAS  PubMed  Google Scholar 

  67. Jonuleit, H., Schmitt, E., Schuler, G., Knop, J. & Enk, A. H. Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J. Exp. Med. 192, 1213–1222 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Richards, D. F., Fernandez, M., Caulfield, J. & Hawrylowicz, C. M. Glucocorticoids drive human CD8+ T cell differentiation towards a phenotype with high IL-10 and reduced IL-4, IL-5 and IL-13 production. Eur. J. Immunol. 30, 2344–2354 (2000).

    CAS  PubMed  Google Scholar 

  69. Miller, C., Ragheb, J. A. & Schwartz, R. H. Anergy and cytokine-mediated suppression as distinct superantigen-induced tolerance mechanisms in vivo. J. Exp. Med. 190, 53–64 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Vieira, P. L. et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J. Immunol. 172, 5986–5993 (2004). This study shows that IL-10-secreting regulatory T cells, unlike naturally occurring T Reg cells, do not express FOXP3, but both populations have a comparable ability to inhibit the proliferation of naive T cells.

    CAS  PubMed  Google Scholar 

  71. Akdis, C. A., Blesken, T., Akdis, M., Wuthrich, B. & Blaser, K. Role of interleukin 10 in specific immunotherapy. J. Clin. Invest. 102, 98–106 (1998). This is a comprehensive early study that shows the association of IL-10 production with tolerance to allergen. The authors provide evidence for IL-10 production in response to allergen following successful allergen immunotherapy of bee-keepers who had become tolerant following repeated stings and of non-atopic individuals.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Akbari, O., DeKruyff, R. H. & Umetsu, D. T. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nature Immunol. 2, 725–731 (2001).

    CAS  Google Scholar 

  73. Akbari, O. et al. Antigen-specific regulatory T cells develop via the ICOS–ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nature Med. 8, 1024–1032 (2002). References 72 and 73 are studies from the same research group that identify pulmonary DCs and T cells as important sources of IL-10 in the lungs and identify the role of IL-10 in the induction of respiratory tolerance.

    CAS  PubMed  Google Scholar 

  74. Boussiotis, V. A. et al. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J. Clin. Invest. 105, 1317–1325 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Gerosa, F. et al. CD4+ T cell clones producing both interferon-γ and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin. Immunol. 92, 224–234 (1999).

    CAS  PubMed  Google Scholar 

  76. Trinchieri, G. Regulatory role of T cells producing both interferon γ and interleukin 10 in persistent infection. J. Exp. Med. 194, F53–F57 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Kullberg, M. C. et al. Bacteria-triggered CD4+ T regulatory cells suppress Helicobacter hepaticus-induced colitis. J. Exp. Med. 196, 505–515 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Pasare, C. & Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033–1036 (2003).

    CAS  PubMed  Google Scholar 

  79. Akdis, M. et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J. Exp. Med. 199, 1567–1575 (2004). This is a recent study showing that IL-10-secreting regulatory T cells are the dominant cell subset that is specific for common environmental allergens in healthy individuals, whereas there is a high frequency of allergen-specific IL-4-secreting T cells in allergic individuals.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Hawrylowicz, C. Correction of the defect in glucocorticoid-induced IL-10 synthesis in T cells from glucocorticoid resistant asthmatic patients. J. Allergy Clin. Immunol. 113 (Suppl.), A735 (2004). This study shows that vitamin D 3 and IL-10 can restore the reactivity of T cells from steroid-resistant patients to glucocorticoids and thereby induce IL-10 synthesis.

    Google Scholar 

  81. Francis, J. N., Till, S. J. & Durham, S. R. Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy. J. Allergy Clin. Immunol. 111, 1255–1261 (2003).

    CAS  PubMed  Google Scholar 

  82. Robinson, D. S., Larche, M. & Durham, S. R. TRegs and allergic disease. J. Clin. Invest. 114, 1389–1397 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genet. 27, 20–21 (2001).

    CAS  PubMed  Google Scholar 

  84. Wildin, R. S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nature Genet. 27, 18–20 (2001).

    CAS  PubMed  Google Scholar 

  85. Chatila, T. A. et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity–allergic disregulation syndrome. J. Clin. Invest. 106, R75–R81 (2000). References 83–85 show that mutations in the human FOXP3 gene are associated with immune dysregulation and disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Grindebacke, H. et al. Defective suppression of TH2 cytokines by CD4CD25 regulatory T cells in birch allergics during birch pollen season. Clin. Exp. Allergy 34, 1364–1372 (2004).

    CAS  PubMed  Google Scholar 

  87. Suto, A. et al. Role of CD4+ CD25+ regulatory T cells in T helper 2 cell-mediated allergic inflammation in the airways. Am. J. Respir. Crit. Care Med. 164, 680–687 (2001).

    CAS  PubMed  Google Scholar 

  88. Jaffar, Z., Sivakuru, T. & Roberts, K. CD4+CD25+ T cells regulate airway eosinophilic inflammation by modulating the TH2 cell phenotype. J. Immunol. 172, 3842–3849 (2004).

    CAS  PubMed  Google Scholar 

  89. Curotto de Lafaille, M. A. et al. Hyper immunoglobulin E response in mice with monoclonal populations of B and T lymphocytes. J. Exp. Med. 194, 1349–1359 (2001).

    CAS  PubMed  Google Scholar 

  90. Ostroukhova, M. et al. Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3. J. Clin. Invest. 114, 28–38 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Fiorentino, D. F., Bond, M. W. & Mosmann, T. R. Two types of mouse T helper cell. IV. TH2 clones secrete a factor that inhibits cytokine production by TH1 clones. J. Exp. Med. 170, 2081–2095 (1989).

    CAS  PubMed  Google Scholar 

  92. Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001). This is a comprehensive review of the biology of IL-10.

    CAS  PubMed  Google Scholar 

  93. Fiorentino, D. F. et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by TH1 cells. J. Immunol. 146, 3444–3451 (1991).

    CAS  PubMed  Google Scholar 

  94. de Waal Malefyt, R. et al. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J. Exp. Med. 174, 915–924 (1991).

    CAS  PubMed  Google Scholar 

  95. Gazzinelli, R. T., Oswald, I. P., James, S. L. & Sher, A. IL-10 inhibits parasite killing and nitrogen oxide production by IFN-γ-activated macrophages. J. Immunol. 148, 1792–1796 (1992).

    CAS  PubMed  Google Scholar 

  96. Buelens, C. et al. Interleukin-10 prevents the generation of dendritic cells from human peripheral blood mononuclear cells cultured with interleukin-4 and granulocyte/macrophage-colony-stimulating factor. Eur. J. Immunol. 27, 756–762 (1997).

    CAS  PubMed  Google Scholar 

  97. Gerber, J. S. & Mosser, D. M. Reversing lipopolysaccharide toxicity by ligating the macrophage Fcγ receptors. J. Immunol. 166, 6861–6868 (2001).

    CAS  PubMed  Google Scholar 

  98. de Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C. G. & de Vries, J. E. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J. Exp. Med. 174, 1209–1220 (1991).

    CAS  PubMed  Google Scholar 

  99. Edwards, A. D. et al. Microbial recognition via Toll-like receptor-dependent and -independent pathways determines the cytokine response of murine dendritic cell subsets to CD40 triggering. J. Immunol. 169, 3652–3660 (2002).

    CAS  PubMed  Google Scholar 

  100. McGuirk, P., McCann, C. & Mills, K. H. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J. Exp. Med. 195, 221–231 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Grunig, G. et al. Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis. J. Exp. Med. 185, 1089–1099 (1997). This was the first report to describe that IL-10 inhibits allergic, as well as T H 1, responses in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Asadullah, K., Sterry, W. & Volk, H. D. Interleukin-10 therapy — review of a new approach. Pharmacol. Rev. 55, 241–269 (2003). This is a comprehensive review of clinical studies involving IL-10.

    CAS  PubMed  Google Scholar 

  103. Arock, M., Zuany-Amorim, C., Singer, M., Benhamou, M. & Pretolani, M. Interleukin-10 inhibits cytokine generation from mast cells. Eur. J. Immunol. 26, 166–70 (1996).

    CAS  PubMed  Google Scholar 

  104. Royer, B. et al. Inhibition of IgE-induced activation of human mast cells by IL-10. Clin. Exp. Allergy 31, 694–704 (2001).

    CAS  PubMed  Google Scholar 

  105. Takanaski, S. et al. Interleukin 10 inhibits lipopolysaccharide-induced survival and cytokine production by human peripheral blood eosinophils. J. Exp. Med. 180, 711–715 (1994). References 103–105 are early studies showing that IL-10 inhibits T H 2-response-regulated effector mechanisms associated with allergy, as well as T H 1 responses.

    CAS  PubMed  Google Scholar 

  106. Nouri-Aria, K. T. et al. Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J. Immunol. 172, 3252–3259 (2004).

    CAS  PubMed  Google Scholar 

  107. Jeannin, P., Lecoanet, S., Delneste, Y., Gauchat, J. F. & Bonnefoy, J. Y. IgE versus IgG4 production can be differentially regulated by IL-10. J. Immunol. 160, 3555–3561 (1998).

    CAS  PubMed  Google Scholar 

  108. Borish, L. et al. Interleukin-10 regulation in normal subjects and patients with asthma. J. Allergy Clin. Immunol. 97, 1288–1296 (1996).

    CAS  PubMed  Google Scholar 

  109. Lim, S., Crawley, E., Woo, P. & Barnes, P. J. Haplotype associated with low interleukin-10 production in patients with severe asthma. Lancet 352, 113 (1998).

    CAS  PubMed  Google Scholar 

  110. Heaton, T. et al. An immunoepidemiological approach to asthma: identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children. Lancet 365, 142–149 (2005). References 108–110 provide evidence for an inverse correlation of IL-10 levels with disease severity.

    CAS  PubMed  Google Scholar 

  111. Stampfli, M. R. et al. Interleukin-10 gene transfer to the airway regulates allergic mucosal sensitization in mice. Am. J. Respir. Cell Mol. Biol. 21, 586–596 (1999).

    CAS  PubMed  Google Scholar 

  112. Oh, J. W. et al. CD4 T-helper cells engineered to produce IL-10 prevent allergen-induced airway hyperreactivity and inflammation. J. Allergy Clin. Immunol. 110, 460–468 (2002).

    CAS  PubMed  Google Scholar 

  113. Fuchs, A. C. et al. Clinical, hematologic, and immunologic effects of interleukin-10 in humans. J. Clin. Immunol. 16, 291–303 (1996).

    CAS  PubMed  Google Scholar 

  114. Norman, P. S. Immunotherapy: past and present. J. Allergy Clin. Immunol. 102, 1–10 (1998).

    CAS  PubMed  Google Scholar 

  115. Bousquet, J. et al. Allergen immunotherapy: therapeutic vaccines for allergic diseases. World Health Organization. American Academy of Allergy, Asthma and Immunology. Ann. Allergy Asthma Immunol. 81, 401–405 (1998).

    CAS  PubMed  Google Scholar 

  116. Norman, P. S. Immunotherapy: 1999–2004. J. Allergy Clin. Immunol. 113, 1013–1023 (2004).

    CAS  PubMed  Google Scholar 

  117. Wilson, D. R., Torres, L. I. & Durham, S. R. Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst. Rev. 2, CD002893 (2003).

    Google Scholar 

  118. Moller, C. et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J. Allergy Clin. Immunol. 109, 251–256 (2002).

    PubMed  Google Scholar 

  119. Pajno, G. B., Barberio, G., De Luca, F., Morabito, L. & Parmiani, S. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin. Exp. Allergy 31, 1392–1397 (2001).

    CAS  PubMed  Google Scholar 

  120. Casale, T. B. Status of immunotherapy: current and future. J. Allergy Clin. Immunol. 113, 1036–1039 (2004).

    PubMed  Google Scholar 

  121. Jutel, M. et al. Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-γ secretion in specific allergen-stimulated T cell cultures. J. Immunol. 154, 4187–4194 (1995). This was the first study to show that allergen immunotherapy is associated with a switch from a T H 2 phenotype towards a T H 1 phenotype.

    CAS  PubMed  Google Scholar 

  122. Ebner, C. et al. Immunological changes during specific immunotherapy of grass pollen allergy: reduced lymphoproliferative responses to allergen and shift from TH2 to TH1 in T-cell clones specific for Phl p 1, a major grass pollen allergen. Clin. Exp. Allergy 27, 1007–1015 (1997).

    CAS  PubMed  Google Scholar 

  123. Wachholz, P. A. et al. Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral TH1:TH2 cytokine ratios. Immunology 105, 56–62 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Soderlund, A. et al. Allergen induced cytokine profiles in type I allergic individuals before and after immunotherapy. Immunol. Lett. 57, 177–181 (1997).

    CAS  PubMed  Google Scholar 

  125. van Bever, H. P., Vereecke, I. F., Bridts, C. H., De Clerck, L. S. & Stevens, W. J. Comparison between the in vitro cytokine production of mononuclear cells of young asthmatics with and without immunotherapy (IT). Clin. Exp. Allergy 28, 943–949 (1998).

    CAS  PubMed  Google Scholar 

  126. Klimek, L. et al. Short-term preseasonal birch pollen allergoid immunotherapy influences symptoms, specific nasal provocation and cytokine levels in nasal secretions, but not peripheral T-cell responses, in patients with allergic rhinitis. Clin. Exp. Allergy 29, 1326–1335 (1999).

    CAS  PubMed  Google Scholar 

  127. Cook, D. N., Pisetsky, D. S. & Schwartz, D. A. Toll-like receptors in the pathogenesis of human disease. Nature Immunol. 5, 975–979 (2004).

    CAS  Google Scholar 

  128. Bellinghausen, I. et al. Insect venom immunotherapy induces interleukin-10 production and a TH2-to-TH1 shift, and changes surface marker expression in venom-allergic subjects. Eur. J. Immunol. 27, 1131–1139 (1997).

    CAS  PubMed  Google Scholar 

  129. Till, S. J., Francis, J. N., Nouri-Aria, K. & Durham, S. R. Mechanisms of immunotherapy. J. Allergy Clin. Immunol. 113, 1025–1034 (2004).

    CAS  PubMed  Google Scholar 

  130. Jutel, M. et al. IL-10 and TGF-β cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur. J. Immunol. 33, 1205–1214 (2003).

    CAS  PubMed  Google Scholar 

  131. Faith, A. et al. Impaired secretion of interleukin-4 and interleukin-13 by allergen-specific T cells correlates with defective nuclear expression of NF-AT2 and jun B: relevance to immunotherapy. Clin. Exp. Allergy 33, 1209–1215 (2003).

    CAS  PubMed  Google Scholar 

  132. Oldfield, W. L., Larche, M. & Kay, A. B. Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial. Lancet 360, 47–53 (2002).

    CAS  PubMed  Google Scholar 

  133. Djurup, R. & Malling, H. J. High IgG4 antibody level is associated with failure of immunotherapy with inhalant allergens. Clin. Allergy 17, 459–468 (1987).

    CAS  PubMed  Google Scholar 

  134. Ewan, P. W., Deighton, J., Wilson, A. B. & Lachmann, P. J. Venom-specific IgG antibodies in bee and wasp allergy: lack of correlation with protection from stings. Clin. Exp. Allergy 23, 647–660 (1993).

    CAS  PubMed  Google Scholar 

  135. Punnonen, J., Aversa, G. G., Vandekerckhove, B., Roncarolo, M. G. & de Vries, J. E. Induction of isotype switching and Ig production by CD5+ and CD10+ human fetal B cells. J. Immunol. 148, 3398–3404 (1992).

    CAS  PubMed  Google Scholar 

  136. Akdis, C. A. et al. Induction and differential regulation of bee venom phospholipase A2-specific human IgE and IgG4 antibodies in vitro requires allergen-specific and nonspecific activation of T and B cells. J. Allergy Clin. Immunol. 99, 345–353 (1997). This is an early report of differential regulation of IgE and IgG4, which led to a series of publications (many of which are highlighted here) proposing that this is an important mechanism associated with successful allergen immunotherapy.

    CAS  PubMed  Google Scholar 

  137. van Neerven, R. J. et al. Blocking antibodies induced by specific allergy vaccination prevent the activation of CD4+ T cells by inhibiting serum-IgE-facilitated allergen presentation. J. Immunol. 163, 2944–2952 (1999).

    CAS  PubMed  Google Scholar 

  138. Wachholz, P. A. & Durham, S. R. Induction of 'blocking' IgG antibodies during immunotherapy. Clin. Exp. Allergy 33, 1171–1174 (2003).

    CAS  PubMed  Google Scholar 

  139. Wachholz, P. A., Soni, N. K., Till, S. J. & Durham, S. R. Inhibition of allergen–IgE binding to B cells by IgG antibodies after grass pollen immunotherapy. J. Allergy Clin. Immunol. 112, 915–922 (2003).

    CAS  PubMed  Google Scholar 

  140. Valenta, R. & Kraft, D. From allergen structure to new forms of allergen-specific immunotherapy. Curr. Opin. Immunol. 14, 718–727 (2002).

    CAS  PubMed  Google Scholar 

  141. Kuehr, J. et al. Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis. J. Allergy Clin. Immunol. 109, 274–280 (2002).

    CAS  PubMed  Google Scholar 

  142. Rolinck-Werninghaus, C. et al. The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children. Allergy 59, 973–979 (2004).

    CAS  PubMed  Google Scholar 

  143. Maurer, D. et al. The high affinity IgE receptor (FcεRI) mediates IgE-dependent allergen presentation. J. Immunol. 154, 6285–6290 (1995).

    CAS  PubMed  Google Scholar 

  144. Novak, N., Bieber, T. & Katoh, N. Engagement of FcεRI on human monocytes induces the production of IL-10 and prevents their differentiation in dendritic cells. J. Immunol. 167, 797–804 (2001). References 143 and 144 provide evidence that crosslinking of IgE regulates APC function.

    CAS  PubMed  Google Scholar 

  145. Larche, M. & Kay, A. B. Peptide therapy and asthma. Am. J. Respir. Crit. Care Med. 169, 1331–1332 (2004).

    PubMed  Google Scholar 

  146. Norman, P. S. et al. Treatment of cat allergy with T-cell reactive peptides. Am. J. Respir. Crit. Care Med. 154, 1623–1628 (1996).

    CAS  PubMed  Google Scholar 

  147. Muller, U. et al. Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom. J. Allergy Clin. Immunol. 101, 747–754 (1998).

    CAS  PubMed  Google Scholar 

  148. Haselden, B. M., Kay, A. B. & Larche, M. Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions. J. Exp. Med. 189, 1885–1894 (1999). References 147 and 148 are independent studies that were the first to describe the successful use of peptides derived from allergen for use in allergen immunotherapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Oldfield, W. L., Kay, A. B. & Larche, M. Allergen-derived T cell peptide-induced late asthmatic reactions precede the induction of antigen-specific hyporesponsiveness in atopic allergic asthmatic subjects. J. Immunol. 167, 1734–1739 (2001).

    CAS  PubMed  Google Scholar 

  150. Ali, F. R., Oldfield, W. L., Higashi, N., Larche, M. & Kay, A. B. Late asthmatic reactions induced by inhalation of allergen-derived T cell peptides. Am. J. Respir. Crit. Care Med. 169, 20–26 (2004).

    PubMed  Google Scholar 

  151. Fellrath, J. M. et al. Allergen-specific T-cell tolerance induction with allergen-derived long synthetic peptides: results of a Phase I trial. J. Allergy Clin. Immunol. 111, 854–861 (2003).

    CAS  PubMed  Google Scholar 

  152. Smith, T. R., Alexander, C., Kay, A. B., Larche, M. & Robinson, D. S. Cat allergen peptide immunotherapy reduces CD4 T cell responses to cat allergen but does not alter suppression by CD4 CD25 T cells: a double-blind placebo-controlled study. Allergy 59, 1097–1101 (2004).

    CAS  PubMed  Google Scholar 

  153. Hoyne, G. F., O'Hehir, R. E., Wraith, D. C., Thomas, W. R. & Lamb, J. R. Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in naive and sensitized mice. J. Exp. Med. 178, 1783–1788 (1993).

    CAS  PubMed  Google Scholar 

  154. Ling, E. M. et al. Allergen immunotherapy increases suppressive activity by CD4+CD25, IL-10 producing T cells, but does not affect suppression by CD4+CD25+ T cells. J. Allergy Clin. Immunol. 113 (Suppl.), A333 (2004).

    Google Scholar 

  155. Krieg, A. M. CpG motifs in bacterial DNA and their immune effects. Annu. Rev. Immunol. 20, 709–760 (2002).

    CAS  PubMed  Google Scholar 

  156. Akira, S. & Takeda, K. Toll-like receptor signalling. Nature Rev. Immunol. 4, 499–511 (2004).

    CAS  Google Scholar 

  157. Duramad, O. et al. IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences. Blood 102, 4487–4492 (2003).

    CAS  PubMed  Google Scholar 

  158. Friedberg, J. W. et al. Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: increased interferon-α/β-inducible gene expression, without significant toxicity. Blood 105, 489–495 (2004).

    PubMed  Google Scholar 

  159. Tighe, H. et al. Conjugation of immunostimulatory DNA to the short ragweed allergen Amb a 1 enhances its immunogenicity and reduces its allergenicity. J. Allergy Clin. Immunol. 106, 124–134 (2000).

    CAS  PubMed  Google Scholar 

  160. Marshall, J. D. et al. Immunostimulatory sequence DNA linked to the Amb a 1 allergen promotes TH1 cytokine expression while downregulating TH2 cytokine expression in PBMCs from human patients with ragweed allergy. J. Allergy Clin. Immunol. 108, 191–197 (2001).

    CAS  PubMed  Google Scholar 

  161. Tulic, M. K. et al. Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response. J. Allergy Clin. Immunol. 113, 235–241 (2004).

    CAS  PubMed  Google Scholar 

  162. Simons, F. E., Shikishima, Y., Van Nest, G., Eiden, J. J. & HayGlass, K. T. Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J. Allergy Clin. Immunol. 113, 1144–1151 (2004). References 161 and 162 describe a novel clinical approach (with encouraging early results) that seeks to improve the efficacy of allergen immunotherapy by conjugating allergen with immunostimulatory DNA motifs.

    CAS  PubMed  Google Scholar 

  163. Durez, P. et al. Antiinflammatory properties of mycophenolate mofetil in murine endotoxemia: inhibition of TNF-α and upregulation of IL-10 release. Int. J. Immunopharmacol. 21, 581–587 (1999).

    CAS  PubMed  Google Scholar 

  164. Durez, P. et al. In vivo induction of interleukin 10 by anti-CD3 monoclonal antibody or bacterial lipopolysaccharide: differential modulation by cyclosporin A. J. Exp. Med. 177, 551–555 (1993).

    CAS  PubMed  Google Scholar 

  165. Bergmann, M. & Sautner, T. Immunomodulatory effects of vasoactive catecholamines. Wien. Klin. Wochenschr. 114, 752–761 (2002).

    CAS  PubMed  Google Scholar 

  166. Hasko, G., Deitch, E. A., Szabo, C., Nemeth, Z. H. & Vizi, E. S. Adenosine: a potential mediator of immunosuppression in multiple organ failure. Curr. Opin. Pharmacol. 2, 440–444 (2002).

    CAS  PubMed  Google Scholar 

  167. Corral, L. G. et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-α. J. Immunol. 163, 380–386 (1999).

    CAS  PubMed  Google Scholar 

  168. Sawicka, E. et al. Inhibition of TH1- and TH2-mediated airway inflammation by the sphingosine 1-phosphate receptor agonist FTY720. J. Immunol. 171, 6206–6214 (2003).

    CAS  PubMed  Google Scholar 

  169. Schafer, P. H. et al. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J. Pharmacol. Exp. Ther. 305, 1222–1232 (2003).

    CAS  PubMed  Google Scholar 

  170. Casnici, C., Lattuada, D., Franco, P., Cattaneo, L. & Marelli, O. Regulation of human peripheral blood lymphocytes IL-10 by SMS 201-995. J. Neuroimmunol. 149, 210–216 (2004).

    CAS  PubMed  Google Scholar 

  171. Wan, S., LeClerc, J. L. & Vincent, J. L. Cytokine responses to cardiopulmonary bypass: lessons learned from cardiac transplantation. Ann. Thorac. Surg. 63, 269–276 (1997).

    CAS  PubMed  Google Scholar 

  172. John, M. et al. Inhaled corticosteroids increase interleukin-10 but reduce macrophage inflammatory protein-1α, granulocyte–macrophage colony-stimulating factor and interferon-γ release from alveolar macrophages in asthma. Am. J. Respir. Crit. Care Med. 157, 256–262 (1998).

    CAS  PubMed  Google Scholar 

  173. Hawrylowicz, C., Richards, D., Loke, T. K., Corrigan, C. & Lee, T. A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients. J. Allergy Clin. Immunol. 109, 369–370 (2002). This paper provides evidence that correlates failure to respond clinically to glucocorticoid treatment with a defect in T-cell responsiveness to glucocorticoids that results in reduced IL-10 expression in vitro.

    CAS  PubMed  Google Scholar 

  174. Peek, E. et al. Combining long-acting β2-agonists and glucocorticoids induces greater inhibition of allergen-specific TH2 cytokine responses and enhances IL-10 responses. J. Allergy Clin. Immunol. 113 (Suppl.), A753 (2004).

    Google Scholar 

  175. Canning, M. O., Grotenhuis, K., de Wit, H. J. & Drexhage, H. A. Opposing effects of dehydroepiandrosterone and dexamethasone on the generation of monocyte-derived dendritic cells. Eur. J. Endocrinol. 143, 687–695 (2000).

    CAS  PubMed  Google Scholar 

  176. Dong, X., Bachman, L. A., Kumar, R. & Griffin, M. D. Generation of antigen-specific, interleukin-10-producing T-cells using dendritic cell stimulation and steroid hormone conditioning. Transpl. Immunol. 11, 323–333 (2003).

    CAS  PubMed  Google Scholar 

  177. McGuirk, P. & Mills, K. H. Pathogen-specific regulatory T cells provoke a shift in the TH1/TH2 paradigm in immunity to infectious diseases. Trends Immunol. 23, 450–455 (2002).

    CAS  PubMed  Google Scholar 

  178. Zuany-Amorim, C. et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nature Med. 8, 625–629 (2002).

    CAS  PubMed  Google Scholar 

  179. Ulisse, S. et al. Expression of cytokines, inducible nitric oxide synthase, and matrix metalloproteinases in pouchitis: effects of probiotic treatment. Am. J. Gastroenterol. 96, 2691–2699 (2001).

    CAS  PubMed  Google Scholar 

  180. Kalliomaki, M., Salminen, S., Poussa, T., Arvilommi, H. & Isolauri, E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet 361, 1869–1871 (2003).

    PubMed  Google Scholar 

  181. Kalliomaki, M. & Isolauri, E. Role of intestinal flora in the development of allergy. Curr. Opin. Allergy Clin. Immunol. 3, 15–20 (2003).

    CAS  PubMed  Google Scholar 

  182. Cottrez, F., Hurst, S. D., Coffman, R. L. & Groux, H. T regulatory cells 1 inhibit a TH2-specific response in vivo. J. Immunol. 165, 4848–4853 (2000).

    CAS  PubMed  Google Scholar 

  183. Hansen, G. et al. CD4+ T helper cells engineered to produce latent TGF-β1 reverse allergen-induced airway hyperreactivity and inflammation. J. Clin. Invest. 105, 61–70 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Arkwright, P. D. & David, T. J. Effect of Mycobacterium vaccae on atopic dermatitis in children of different ages. Br. J. Dermatol. 149, 1029–1034 (2003).

    CAS  PubMed  Google Scholar 

  185. Gorelik, L. & Flavell, R. A. Transforming growth factor-β in T-cell biology. Nature Rev. Immunol. 2, 46–53 (2002).

    CAS  Google Scholar 

  186. Tiemessen, M. M. et al. CD4 CD25 regulatory T cells are not functionally impaired in adult patients with IgE-mediated cow's milk allergy. J. Allergy Clin. Immunol. 110, 934–936 (2002).

    PubMed  Google Scholar 

  187. Idzko, M. et al. Expression and function of histamine receptors in human monocyte-derived dendritic cells. J. Allergy Clin. Immunol. 109, 839–846 (2002).

    CAS  PubMed  Google Scholar 

  188. Kunzmann, S. et al. Histamine enhances TGF-β1-mediated suppression of TH2 responses. FASEB J. 17, 1089–1095 (2003).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We gratefully acknowledge helpful discussions with A. Faith, at King's College London (United Kingdom), and D. Robinson, at Imperial College London. C.M.H. is supported, in part, by grants from Asthma UK and from Euro-Thymaide (European Union).

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DATABASES

Entrez Gene

CD4

CD25

CTLA4

FOXP3

GITR

IL-4

IL-5

IL-9

IL-10

IL-13

TGF-β

Glossary

ALLERGIC

Having a clinically evident reaction to ubiquitous allergens, which is reflected by acquired immune responses that are marked, phenotypically, by the presence of allergen-specific IgE, together with mast-cell and eosinophil recruitment and activation. CD4+ T cells producing a T-helper-2 profile of cytokines (interleukin-4 (IL-4), IL-5, IL-9 and IL-13) are thought to be central to the development of allergic responses.

RHINITIS

Inflammation of the mucous-membrane lining of the nose. The membrane becomes swollen, leading to partial or complete obstruction of air-flow, with excess local mucus production.

ATOPIC DERMATITIS

A chronic skin disease in which the skin becomes extremely itchy and inflamed, causing redness, swelling, cracking, weeping, crusting and scaling. Its multifactorial pathogenesis involves genetic susceptibility, environmental triggers and immune dysregulation (typically dominated by T-helper-2 cells), with the involvement of IgE contributing to its classification as an atopic disease.

ANAPHYLAXIS

The generalized release of histamine and other inflammatory mediators following systemic induction of mast-cell degranulation by allergen. Anaphylaxis can cause bronchospasm, cardiovascular collapse and death.

ATOPY

The development of strong IgE responses to common environmental antigens.

GLUCOCORTICOIDS

Hormones produced by the adrenal gland. Synthetic derivatives are commonly used to suppress a wide range of inflammatory conditions and are used topically, intranasally or orally for the control of allergic and asthmatic reactions. Commonly used derivatives include fluticasone and prednisolone.

ALLERGEN-DESENSITIZATION THERAPY

Allergen immunotherapy was introduced in the early 1900s. In general, it involves subcutaneous injection of increasing doses of specific allergen into the patient. This is carried out under carefully controlled clinical conditions because of the potential for life-threatening adverse reactions. On average, it results in 50% reduction of clinical symptoms and medication usage, and it also results in beneficial modifications of the patient's immune response to allergen. Following the initial course of injections (either conventional or rushed), patients receive maintenance injections (less frequently) of allergen for optimal clinical benefit.

CLASS SWITCHING

The somatic-recombination process by which immunoglobulin isotypes are switched from IgM to IgG, IgA or IgE.

β2 AGONISTS

β2-Adrenergic receptors are expressed by smooth-muscle cells, mast cells, endothelial cells, epithelial cells and a range of inflammatory cells. Short-acting agonists of these receptors (for example, albuterol) and long-acting agonists (for example, salmeterol (Serevent; GlaxoSmithKline) and formeterol) are used to induce bronchodilation in patients with asthma. Long-acting derivatives are also proposed to have anti-inflammatory properties.

AIRWAY HYPER-RESPONSIVENESS

(AHR). An abnormally increased sensitivity of the airways to otherwise innocuous stimuli, resulting in increased responses to inhaled allergen and airway smooth-muscle spasmogens (for example, methacholine or histamine). In humans, this is generally defined by PC20 (the provocation concentration of the spasmogen that causes a 20% decrease in FEV1: that is, the forced expiratory volume in 1 second). Current hypotheses regarding the underlying process include mechanisms that lead to thickening of the airway wall, swelling of the airway-wall lining, epithelial damage that causes exposure of sensory nerve-fibre endings or changes in the contractile properties of smooth muscle.

SUBLINGUALLY

Local application in the mouth, with or without swallowing. For allergen immunotherapy, sublingual application is less commonly used than subcutaneous injection. It is proposed to be associated with fewer systemic adverse events, but it might be less effective. The clinical efficacy is thought to range from 20% to 50% based on the reduction of symptom scores and medication usage.

IMMUNODOMINANT EPITOPES

Epitopes present in a complex mixture of proteins (such as provided by a whole virus, tumour cell, bacterium or allergen) that induce strong T-cell responses.

CRYPTIC EPITOPES

Antigenic peptides that are generated at sub-threshold levels or do not normally form epitopes after antigen processing. When cryptic epitopes become 'visible' to the immune system, they can elicit an immune response that induces autoimmune disease and possibly allergy.

CpG MOTIFS

DNA oligonucleotide sequences that include a cytosine– guanosine sequence and certain flanking nucleotides. They have been found to induce innate immune responses through interaction with Toll-like receptor 9. Also known as immunostimulatory oligodeoxynucleotides (ISS ODNs).

SKIN-PRICK TESTING

Clinical investigation to determine allergic sensitivity to various substances by injecting small quantities into or under the skin. A positive response is measured by the size of a red wheal and compared with reactions caused by histamine and saline as positive- and negative-control reactions.

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Hawrylowicz, C., O'Garra, A. Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nat Rev Immunol 5, 271–283 (2005). https://doi.org/10.1038/nri1589

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